Water-based delivery systems

ABSTRACT

The invention relates to a water-based delivery system for an active substance, characterized by enhancing skin barrier restoration in the stratum corneum comprising water, a fatty acid, cholesterol, a ceramide and at least one skin lipid precursor.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/365,059, filed Mar. 13, 2002, which is incorporatedherein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to a novel topical and mucosaldelivery systems for drugs or any other active substance.

BACKGROUND OF THE INVENTION

[0003] The main demands on human skin are to prevent loss of water, andto prevent water and other matter of the environment from entering thebody indiscriminately. The human skin thus forms a selectivelypermissible physical barrier between the human body and itssurroundings.

[0004] The barrier function has been shown to reside in the stratumcorneum. The stratum corneum is the topmost layer of the skin, and isbuilt of corneocytes. Corneocytes are cells that contain extensivelycross-linked proteins, surrounded by a highly resistant cell envelope.The corneocytes are embedded in a bed of specific lipid structures oflong chain lipids. These long chain lipids are organized as bilamellarstructures stacked on top of each other. The bilamellar structures fillthe intercellular spaces between the corneocytes.

[0005] To account for the skin's barrier properties, and for itsselective hydrophilic and hydrophobic pathways, the skin has beendescribed as a mosaic barrier model. This model envisages barrier lipidsto exist predominantly in crystalline (gel) form. Such a form provideswater impermeable domains, which are surrounded by so-called grainborders of lipids in a liquid crystalline state. This arrangementprovides an effective, water tight barrier that still allows a minutebut controlled loss of water through the liquid crystallineinterdomains. This controlled water loss is enough to keep the keratinof the stratum corneum hydrated. The liquid character of the interdomaingrain borders allows passage of hydrophilic and hydrophobic molecules ondown-hill gradients, i.e. passage by passive diffusion.

[0006] Dermal delivery systems are compositions which deliver activesubstances to, or through, the skin. These compositions typicallycontain skin permeation enhancers. Permeation enhancers may inducestructural transformations of the bilamellar structure in the liquidcrystalline interdomain regions, and thus promote transdermal deliveryof, for example, pharmacological substances.

[0007] Typical dermal delivery systems have an alcohol or petroleumbase, with little consideration given to the biological properties ofthe vehicle itself. For example, emulsified fatty acids can inheritcertain detergent properties if their structure is significantly alteredfrom those in the normal skin. The detergent properties can lead todisruption of the normal barrier function, which is counteractive to thepotential benefit of the delivery system. Disruption of the normalbarrier function often causes the stratum corneum to lose its naturalpotential to function properly as a barrier. As a result, the skinbecomes either too dry or too permeable to environmental substances.

[0008] Other conventional delivery systems that are thought to protectthe skin from harmful substances are barrier ointments. The purpose ofbarrier ointments is to provide a film, and thereby create a layer whichis impermeable to environmental substances. Due to the impermeability,though, these ointments both increase the body temperature of thetreated body part, as well as prevent perspiration, and thus render anuncomfortable sensation.

[0009] The dermal delivery systems described above are not formulated todeliver a substance to, or through, the human skin without permanentlydisrupting the stratum corneum's natural barrier function.

SUMMARY OF THE INVENTION

[0010] In one embodiment, the invention relates to a water-baseddelivery system for an active substance, characterized by enhancing skinbarrier restoration in the stratum corneum comprising water, a fattyacid, cholesterol, and a ceramide. In another embodiment, the deliverysystem also comprises at least one skin lipid precursor.

[0011] In an additional embodiment, the invention relates to deliverysystem for an active substance comprising water and lipophiliccomponents, wherein the lipophilic components comprise fatty acids,cholesterol, and a ceramide/phospholipid portion, and wherein thelipophilic components are in the form of lipid particles, and gasspheres or vesicles. This delivery system can also comprise at least oneskin lipid precursor.

BRIEF DESCRIPTION OF DRAWINGS

[0012]FIG. 1 is a diagram showing the gas spheres, lipid particles,vesicles and hydrophilic phase of the delivery systems.

[0013]FIG. 2 is a diagram showing the components of the gas spheres ofthe delivery systems.

[0014]FIG. 3 is a diagram showing the components of the lipid particlesand of the vesicles of the delivery systems.

[0015]FIG. 4 is a diagram showing the location of active substanceswithin the various microcompartments of the delivery systems.

DETAILED DESCRIPTION OF INVENTION

[0016] The present invention provides an improved topical deliverysystem (skin preparation) formulated to deliver a substance to, orthrough, the human skin without permanently disrupting the stratumcorneum's natural barrier function. Additionally, the topical deliverysystem of the present invention provides unique skin barrier restorationproperties.

[0017] All percentages given below are indicated in percent by weight.All numbers are approximate.

[0018] The topical delivery system of the present invention is awater-based formulation comprising hydrophilic and lipophiliccomponents. In a preferred embodiment, the delivery system comprises awater content exceeding 50%, such as more than 55%, 60%, 65%, 70%, 75%,76%, 77%, 78%, 79%, 80%, 85%, 87%, 90%, 94%, 95% and 98%. Preferably,the water content is between 60-80%, more preferably, between 70 and80%.

[0019] The topical delivery system is preferably designed, in its choiceand composition of lipids, to resemble the normal lipid organization ofthe stratum corneum (horny layer), as much as possible. Uponadministration, the system (formulation) blends with the lipidsnaturally present in the stratum comeum, and easily penetrates the lipidbilayer of the skin. In doing so, the system carries along with it oneor more active substances to be administered. The system enhancespenetration of active substances into and/or through the stratumcorneum, while the normal barrier properties of the stratum corneum areleft intact, and/or are even functionally enhanced.

[0020] The lipophilic component (i.e. lipids) of the system comprisesfatty acids, cholesterol and a ceramide/phospholipid portion. The lipidsare similar to those which make up the normal stratum comeum. Thepreferred ratio of the ceramide/phospholipid portion:cholesterol:fattyacid is in the range of approximately 2:1:1.5 to approximately2.95:0.5:0.5. Preferably, for example, the ratio is approximately 2:1:1;more preferably the ratio is approximately 2.35:1:1.

[0021] The fatty acids of the present invention can be any fatty acid,mixtures of fatty acids, salts of fatty acids, or mixtures of fattyacids and salts of fatty acids. The fatty acids can be saturated orunsaturated. Additionally, the fatty acids can comprise precursors offatty acids. In a preferred embodiment, the fatty acids comprise ten,twelve, fourteen, sixteen, eighteen, twenty, twenty-two, or twenty-fourcarbon atoms, or any mixture of such fatty acids. A fatty acid mixturewith a predominant portion of fatty acids which comprise a chain ofsixteen or eighteen carbon atoms is most preferred.

[0022] For example, the delivery system can be prepared from a mixtureof fatty acids of the following composition: at most about 2% of acomponent comprising a chain of fourteen carbon atoms, between about 47and about 52% of a component comprising a chain of sixteen carbon atoms,between about 43 and about 48% of a component comprising a chain ofeighteen carbon atoms, and at most about 1% of a component comprising achain of twenty carbon atoms.

[0023] Examples of suitable saturated fatty acids for use in thedelivery system include lauric acid, myristic acid, palmitic acid,stearic acid, arachidic acid, behenic acid, and lignoceric acid.Examples of suitable unsaturated fatty acids include oleic acid,palmitoleic acid, linoleic acid, linolenic acid, and arachidonic acid.Preferably, the delivery system contains an essential portion, such asabout 90%, of such fatty acids.

[0024] The preferred fatty acids are the essential fatty acids (EFAs).EFAs are essential for the plasma membrane formation of all cells. Inkeratinocytes, EFA deficiency makes cells hyperproliferative.Supplementation of EFAs reverses the hyperproliferation. EFAs alsoenhance lipid biosynthesis of the epidermis and provide lipids for thebarrier formation of the epidermis. The essential fatty acids arepreferably chosen from linoleic acid, γ-linolenic acid, homo-γ-linolenicacid, columbinic acid, eicosa-(n-6,9,13)-trienoic acid, arachidonicacid, timnodonic acid, hexaenoic acid, and mixtures thereof.

[0025] The delivery system also comprises cholesterol, or derivatives ofcholesterol such as, for example, lipid esters of cholesterol.

[0026] The ceramide/phospholipid portion can comprise 100% ceramide,100% phospholipids, or any other percent combination of ceramide andphospholipids. For example, the ceramide/phospholipid portion cancomprise 95% ceramide and 5% phospholipids, 90% ceramide and 10%phospholipids, 85% ceramide and 15% phospholipids, or 80% ceramide and20% phospholipids.

[0027] The ceramide component of the delivery system can be any ceramideor any mixture of ceramides. In this specification, ceramides includepseudoceramides and neoceramides.

[0028] For example, the ceramide may be any of ceramide 1-7; and/ormixtures thereof. 5 Some specific examples of ceramides include ceramide1, ceramide 3, ceramide 4, ceramide 5, ceramide 6A, cerebrosides andceramide 6B.

[0029] Some examples of pseudoceramides include:

[0030] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)hexadecanamide

[0031] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)propanamide

[0032] N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)butanamide

[0033] N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)heptanamide

[0034] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)ethanamide

[0035] N-(2-hydroxyoctadecyl)-N-(2-O-glucopyranosyl)ethylpentanamide

[0036] N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)hexanamide

[0037] N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2butylhexanamide

[0038] N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)ethanamide

[0039] N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2-hydroxyhexanamide

[0040] N-(2-hydroxytetraadecyl)-N-(2-hydroxyethyl)propanamide

[0041] N-(2-hydroxyhexadecyl)-N-(2-sulfoethyl)hexadecanamide

[0042] N-(2-hydroxyoctadecyl)-N-(2-phosphoethyl)butanamide

[0043] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide

[0044]N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyetbyl)hexadecanamide

[0045] N-(2-hydroxy-3-nonanyloxypropyl)-N-(2-hydroxyethyl)propananide

[0046] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide

[0047]N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide

[0048] N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)butanamide

[0049] N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide

[0050]N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-sulfohydroxyethyl)decanamide

[0051] N-(2-hydroxy-3-decyloxypropyl)-N-(2-hydroxyethyl)hexanamide

[0052]N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide

[0053] N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)butanamide

[0054] N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)co-o-linoleoyldocosanamide

[0055] N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide

[0056]N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)-2-methylpropanamide

[0057] N-(2-hydroxy-3-tetraadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide

[0058] N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)heptanamide

[0059]N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-phosphoethyl)hexadecanamide

[0060] N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide

[0061]N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-)-glucopyranosyl)ethyl-2-hydroxypropanamide

[0062] N-(2-hydroxy-3-octyloxypropyl)-N-(2-hydroxyethyl)pentanamide

[0063] Some examples of neoceramides include:

[0064] N-(2,3-dihydroxypropyl)-N-(hexadecyl)butanamide

[0065] N-(2,3-dihydroxypropyl)-N-(tetradecyl)ethanamide

[0066] N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxypropanamide

[0067] N-(2,3-dihydroxypropyl)-N-(octadecyl)butanamide

[0068] N-(2,3-dihydroxypropyl)-N-(2-ethylhexadecyl)hexanamide

[0069] N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyoctanamide

[0070] N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide

[0071] N-(2,3-dihydroxypropyl)-N-(dodecyl)butanamide

[0072] N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyhexanamide

[0073] N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)octanamide

[0074] N-(2-hydroxy-3-phosphopropyl)-N-(octadecyl)ethanamide

[0075] N-(2-hydroxy-3-sulfopropyl)-N-(hexadecyl)butanamide

[0076] N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)decanamide

[0077] N-(2,3-dihydroxypropyl)-N-(heptadecyl)ethanamide

[0078] N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide

[0079] N-(2,3-dihydroxypropyl)-N-(heptadecyl)butanamide

[0080] N-(2,3-dihydroxypropyl)-N-(6-dodecenyl)hexadecan-amide

[0081]N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxy-ethanamide

[0082] N-(2,3-dihydroxypropyl)-N-(ectadecyl)2-hydroxypropan-amide

[0083] N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(heptadecyl)-ethanamide

[0084] N-(2-hydroxy-3-sulfopropyl)-N -(dodecyl)heptanamide

[0085] N-(2,3-dihydroxypropyl)-N-(tetradecyl)-4-hydroxybutanamide

[0086]N-(2,3-dihydroxypropyl)-N-(octadecyl)-(t)-O-linoleoyl-docosanamide

[0087] N-(2,3-dihydroxypropyl)-N-(linoleyl)ethanamide

[0088] N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxy-heptan-amide

[0089] N-(2,3-dihydroxypropyl)-N-iyiodecyl)-(t)-O-linoleoyldocosanamide

[0090] N-(2,3-dihydroxypropyl)-N-(octadecyl)-3-hyrdoxybutanamide

[0091] N-(2-phospho-3hydroxypropyl)-N-(heptadecyl)butanamide

[0092] N-(2,3-dihydroxypropyl)-N-(2-methylheptadecyl)propanamide

[0093] N-(2,3-dihydroxypropyl)-N-(3-ethylheptadecyl)butanamide

[0094] N-(2-sulfo-3-hydroxypropyl)-N-(1-octadecyl)ethanamide

[0095] N-(2,3-dihydroxypropyl)-N-(octadecyl)propanamide

[0096] N-(2,3-dihydroxypropyl)-N-(dodecyl)decanamide

[0097] N-(2,3-dihydroxypropyl)-N-(3-ethyldodecyl)butanamide

[0098] N-(2-O-glucopyranosyl-3-hydroxy propyl)-N-(heptadecyl)butanamide

[0099] N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxypropanamide

[0100] N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxyheptanamide

[0101] N-(2,3-dihydroxypropyl)-N-(dodecyl)-2-hydroxyoctanamide

[0102] N-(2,3-dihydroxypropyl)-N(hexadecyl)-2-methylheptanamide

[0103] N-(2,3-dihydroxypropyl)-N-(octadecyl)-2-hydroxypentanamide

[0104]N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxyheptanamide

[0105] N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxypropanamide

[0106] N-(2;3-dihydroxypropyl)-N-(tetradecyl)ethanamide.

[0107] The phospholipid component may contain any phospholipid ormixtures of phospholipids. Preferably the phospholipid componentcomprises phosphatidylcholine (PC). Other examples of phospholipidsinclude distearoylphosphatidylcholine (DSPC 18), phosphatidic acid,inositol phosphate, phosphatidylglycerol, phosphatidylinositol,phosphatidylserine, and phosphatidylethanolamine.

[0108] Additionally, the phospholipid component can comprise one or morelysophospholipids. Lysophospholipids are single chain phospholipids.Examples of lysophospholipids include lysophosphatidylcholines, such asmonopalmitoylphosphatidylcholine (MPPC); lysophosphatidylglycerols;lysophosphatidylethanolamines; lysophosphatidylinositols;lysophosphatidylserines; and lysophosphatidic acid. Mixtures ofdifferent types of phospholipids and/or lysophospholipids can also beused.

[0109] In a preferred embodiment, the present system also comprises skinlipid precursors. The lipid precursors include any compound thatpromotes in situ cholesterol, ceramide or sphingolipid synthesis. Thepreferred lipid precursors are mevalonic acid, which promotes in situcholesterol synthesis; and 25-hydroxycholecalciferol, which promotes insitu ceramide synthesis in the skin. Other preferred precursors arepalmitoyl CoA and serine, which together are converted to3-ketosphinganine, which promotes in situ ceramide synthesis in theskin.

[0110] By the promotion of in situ cholesterol and ceramide synthesis inthe skin, the overall content of lipid in the system can be maintainedin a range as low as approximately 2-20%. Therefore, the water contentof the delivery system can be as high as 80-98%. The high water contentenables the skin to “breathe” normally, and enhances its ability torestore its normal barrier function rapidly.

[0111] Other lipid precursors useful in the present invention include,for example: acylceramides; deoxyacetein cimifugoside, adapalene,adenosine, aloe derived lectins, 3-aminopropyl dihydrogen phosphate,anise extracts, ascorbic acid and derivatives thereof, ascorbylpalmitate, asiatic acid, benzoic acid derivatives, biotin, butanoylbetulinic acid, cathecholamines, coenzyme Q10, dehydrocholesterol,dehydroascorbic acid and derivatives thereof, estrogen and derivatives,eythrobic acid, genistein, lipoic acid, 4-methoxysalicylic acid,N-acetylcysteine, panthetine, pregnenolone and derivatives, retinal,retinoates, retinal, retinyl acetate, retinyl glucuronate, retinyllinoleate, retinyl palmitate, retinyl proprionate, phytosphingosine,sphingosine, and others.

[0112] Preferably, an alkaline compound, or buffer system, is includedin the formulation to adjust the pH. Examples of alkaline compoundsinclude triethanolamine (TEA), sodium hydroxide, sodium acetate, andsodium bicarbonate. Examples of buffer systems include carbonicacid/potassium carbonate, phosphoric acid/potassium phosphate, andacetic acid/sodium acetate.

[0113] The fatty acids of the final delivery system can be in a freestate or can form a salt. The portion of fatty acids which is in a freestate is partially dependent on the pH of the formulation. In general,the level of free fatty acid increases as the pH of the formulationdecreases. Depending upon the particular use of the formulation, the pHof the formulation can vary. Preferably, the pH of the formulation isabout 6.5 to 7.8.

[0114] In a preferred embodiment, the delivery system comprisestriethanolamine (TEA). It is preferred to adapt the molar ratio betweenthe fatty acids and triethanolamine to enable a certain portion of thefatty acids in the final delivery system to form a triethanolaminiumsalt, while another portion of the acid exists as free fatty acid.Preferably, the delivery system is prepared from fatty acids andtriethanolamine in which the molar ratio of the fatty acids to thetriethanolamine is higher than about 2:1, preferably higher than about3:1.

[0115] In a preferred embodiment, the delivery system comprises acombined content of a fatty acid, cholesterol, a ceramide/phospholipidportion, and skin lipid precursors between about 2-20%. A preferred lowend of this range is about 2%, 3%, 4%, 5%, 6%, 7% or 8%. A preferredhigh end of this range is about 13%, 14%, 15%, 16%, 17%, 18%, 19% and20%.

[0116] In another preferred embodiment, the amounts of the components ofthe delivery system are as follows: fatty acid: 0.5-10%; cholesterol:0.5-10%; a ceramide/phospholipid portion: 0.005-20%; and lipidprecursors: 0.000001-10%.

[0117] In a preferred embodiment, the formulation does not contain anyirritating ingredients. Examples of irritating ingredients includealcohols, such as isopropanol and ethanol; short chain fatty acids; anddetergents. Preferably, the formulation contains less than 10% alcohol,more preferably less than 5% alcohol, most preferably less than 1%alcohol, and optimally no alcohol.

[0118] Without the intention to limit the scope of the invention, apossible theory explaining the mechanical properties of the deliverysystem follows. The administered formulation easily penetrates the lipidbilayer of the skin. In doing so, the system creates a temporary andreversible state of enhanced atrophy among the lipid components of thebilayer. The enhanced atrophy in itself then gives rise to either a)enhanced energy levels, wherein the energy could promote activetransport of the to-be-carried substances into the skin, and/or b)creates naturally and reversibly occurring holes and disorganizedpatches in the lipid bilayer through which the active substances couldthen pass more easily. It is very well feasible that the temporarydisarray in the lipid bilayer will temporarily break up the organizedstructure of the bilayer and create micelles of lipids with areasbetween them, or surrounding them, through which lipophobic/hydrophilicsubstances and/or compositions can enter through the stratum corneum. Asthe lipid composition of the formulation resembles the natural lipidcomposition of the skin, the so introduced new lipids will after a shorttime of creative chaos easily blend in with the natural lipid buildingstones of the lipid bilayer, and thus not permanently damage the barrierfunction of the skin.

[0119] Following the temporary disarray in the lipid bilayer, the normalbarrier function of the cornea stratum rapidly returns. (That is, theskin barrier restoration is rapid.) The rapid return may be enhanced bythe lipid precursors of the formulation. For example, the in situpromotion of cholesterol synthesis in the stratum corneum, the in situpromotion of ceramide synthesis in the stratum corneum, and/or the insitu promotion of sphingolipid synthesis in the stratum corneum mayallow for the rapid skin barrier restoration.

[0120] A delivery system according to the present invention preferablycomprises a combination of: Fatty Acid (C16-24) 0.5-10% Phospholipid0.5-10% Cholesterol 0.5-7% Lipid precursor: 0.000001-10% Mevalonic acidand/or 25-Hydroxycholecalciferol Ceramide 0.005%-7%

[0121] Another preferred embodiment of the delivery system comprises:Fatty Acid (C16-24) 0.5-10% Phospholipid 0.5-10% Cholesterol 0.5-7%Lipid precursor: 0.000001-10% Mevalonic acid and/or25-Hydroxycholecalciferol Ceramide 0.005%-7% Glycerine 0-5% Propyleneglycol 0-48% PVP (e.g., M weight 40.000) 0-5% TEA 0-3%

[0122] An even more preferred embodiment of the delivery systemcomprises: Fatty Acid (C16-24) 2% Phospholipid 4.5% Cholesterol 2% Lipidprecursor: 0.000001-10% Mevalonic acid and/or 1% or 0.01%25-Hydroxycholecalciferol 0.015% or 0.0015% Ceramide 3 0.015% Glycerine3% Propylene glycol 4% PVP (M weight 40.000) 2% TEA 0.5%

[0123] An even more preferred embodiment of the delivery systemcomprises: Fatty Acid (C16-24) 2% Phospholipid 4.5% Cholesterol 2% Lipidprecursor: 0.000001-10% Mevalonic acid and/or 1% or 0.01%25-Hydroxycholecalciferol 0.015% or 0.0015% Ceramide 3 0.015% Glycerine3% Propylene glycol 4% PVP (M weight 40.000) 2% TEA 0.5% Ceramide 10.025%

[0124] The topical delivery system according to the present inventionfurther comprises one or more cosmetically and/or therapeutically activesubstances. Active substances are defined as agents other thanemollients and other than ingredients that merely improve the physicalcharacteristics of the formulation.

[0125] Some general examples of active substances include sunscreens,tanning agents, skin anti-wrinkling agents, anti-dandruff agents,anti-acne agents, hair growth stimulants and vitamins. Therapeuticallyactive substances include, but are not limited to, substances whichtreat conditions such as eczema, dry skin, itchy skin, fungal infection,acne, skin cancer, hair loss, louse infection, psoriasis, and skinlesions (i.e. wounds). Therapeutically active substances also includesubstances for transdermal delivery, for example, interleukin, hormones,vaccines, nicotine, interferon, pain killers, peptides, proteins andvitamins.

[0126] Active substances also include steroid hormones. Steroid hormonesinhibit inflammation and hyperproliferation of the epidermis thusresulting in normalization of hypersensitive skin conditions. Examplesof steroid hormones include, but are not limited to, glucocorticoids,androgens and estrogens.

[0127] Examples of sunscreens include those materials commonly employedto block ultraviolet light. Illustrative compounds are derivatives ofPABA, cinnamate and salicylate. For example, octyl methoxycinnamate and2-hydroxy-4-methoxybenzophenone (also known as oxybenzone) can be used.Octyl methoxycinnamate and 2-hydroxy-4-methoxybenzophenone arecommercially available under the trademarks, Parsol MCX andBenzophenone-3, respectively. The exact amount of sunscreen employed inthe systems can vary depending upon the degree of protection desiredfrom the sun's UV radiation.

[0128] Examples of vitamins include vitamin A and vitamin E, preferablyin the form of an ester of a fatty acid, such as vitamin A palmitate(retinyl palmitate) and vitamin E linoleate (tocopheryl linoleate).Other esters of vitamins A and E may also be utilized, such as any ofthe fatty acids mentioned above and below.

[0129] Preservatives may also be included in the formulations of thepresent invention. Suitable preservatives include alkyl esters ofp-hydroxybenzoic acid, hydantoin derivatives, propionate salts, and avariety of quaternary ammonium compounds. Particularly preferredpreservatives of this invention are methyl paraben, propyl paraben,imidazolidinyl urea, sodium dehydroxyacetate and benzyl alcohol.Preservatives are typically used in amounts up to about 2% by weight ofthe formulation.

[0130] Other adjunct minor components may also be incorporated into theformulations of the present invention. These components may includethickeners, coloring agents, opacifiers and perfumes. For example, anythickening agent can be included in the formulation to adjust theviscosity of the formulation. Examples of suitable thickening agentsinclude glycerol and xanthan gum. Some additional adjunct minorcomponents include chalk, talc, Fullers earth, kaolin, starch, smectitesclays, chemically modified magnesium aluminium silicate, organicallymodified montmorillonite clay, hydrated aluminium silicate, fumedsilica, aluminium starch octenyl succinate and mixtures thereof. Amountsof these adjunct minor components may range anywhere from 0.001 up to20% by weight of the formulation (i.e. composition).

[0131] The delivery system can be in any form, such as a cream, alotion, a gel, and an aerosol foam. The amount of certain adjunct minorcomponents used in a particular formulation varies depending on thedesired form of the delivery system, as would be known by a skilledartisan. For example, the amount of thickening agent used to prepare anaerosol foam formulation is about 10 to 20% of the amount used toprepare a cream formulation. Additionally, emulsifiers are added to anaerosol foam formulation, such as, for example, laureth 4.

[0132] In another embodiment, the present invention provides a mucosaldelivery system formulated to deliver a substance to, or through, ahuman mucous membrane without permanently disturbing the integrity ofthe mucous membrane. The mucous membrane is the moist tissue that linessome organs and body cavities (such as nose, mouth, lungs, rectum,stomach and vagina) and secretes mucous. The mucosal delivery systemcomprises the lipophilic and hydrophilic components, as described above.The particular formulations of the mucosal delivery systems are variedto accommodate the particular environment of the mucosa, as would beknown by a skilled artisan.

[0133] In a preferred embodiment, the lipophilic components of thetopical or mucosal delivery system form three types of particles: gasspheres, vesicles, and lipid particles. These three types of particlesare within a hydrophilic phase (i.e. aqueous medium). See FIG. 1.

[0134] The gas spheres are lipid monolayers that enclose air bubbles.These monolayers are formed from the lipophilic components. Negativelycharged carboxylate groups stud the outer surfaces of these gas spheres.See FIG. 2. Preferably, these gas spheres are approximately 1 μm toapproximately 500 μm in diameter.

[0135] The vesicles are lipid bilayers enclosing a hydrophilic core.These bilayers are formed from the lipophilic components. Negativelycharged carboxylate groups stud the inner and outer surfaces of thevesicles. See FIG. 3. The vesicles can range from approximately 0.02 μmto approximately 0.5 μm in diameter.

[0136] The lipid particles are lipid monolayers enclosing fatty acids.These monolayers are formed from the lipophilic components. See FIG. 3.The lipid particles are less than approximately 1 to approximately 150μm in diameter. The lipid particles may be in the form of individuallipid particles, or the lipid particles may aggregate to form crystals.

[0137] The various particles of the delivery system providemicrocompartments with different properties. Due to these differentmicrocompartments, the delivery system can be used to deliver bothhydrophilic and lipophilic active substances. For example, a watersoluble active substance can be located in the hydrophilic core of thevesicles, or can be located in the hydrophilic phase of the system. Alipid soluble active substance can be located within the monolayer ofthe gas spheres, within the bilayer of the vesicles, or within themonolayer or within the core of the lipid particles. See FIG. 4.

[0138] Preferably, the delivery systems comprise three phases, i.e. afoam phase, a vesicle phase and a hydrophilic phase. The foam phasecomprises the gas spheres and the lipid particles. The vesicle phasecomprises the vesicles and the lipid particles. The hydrophilic phasecomprises water and hydrophilic components.

[0139] In a preferred embodiment, the delivery system is produced fromthree portions (i.e. fractions), in particular a hydrophilic portion andtwo lipophilic portions. The two lipophilic portions comprise thelipophilic components as defined above. Both lipophilic portions areimmersed in aqueous media. One portion is made into the foam phase. Theother portion is made into the vesicle phase. The foam phase portion andthe vesicle phase portion can be in a ratio from about 1:7 to about 7:1.Preferably, the foam phase portion and the vesicle phase portion areapproximately equal in amount.

[0140] Preferably, the foam phase is formed by mixing the foam phaseportion at about 65 to 85° C. The pH is set to the range of about 5.5 to8.2. The mixing is performed under conditions so as to allow gas spheresto form.

[0141] Preferably, the vesicle phase is formed by gently mixing thevesicle phase portion at about 65 to 85° C. The pH is set to the rangeof about 5.5 to 8.2. After mixing, the vesicle phase portion ishomogenized. Homogenization can be accomplished with, for example, ahigh pressure homogenizer or a sonicator. The pressure of thehomogenizer can be set, for example, from about 10,000 to 40,000 psi.Preferably, the vesicle phase is produced under conditions which do notallow any gas to enter the formulation, such as in a vacuum.

[0142] The lipid particles, and/or lipid particle crystals, form as aby-product of the formation of the foam phase and vesicle phase. Ineither the foam phase or vesicle phase, up to 30% of the lipophiliccomponents can be in the form of lipid particles and/or lipid particlecrystals.

[0143] The hydrophilic phase is formed by mixing together water solublecomponents with water (i.e. hydrophilic portion). Examples of watersoluble components include propylene glycol, glycerol,polyvinylpyrrolidone, and thickeners, e.g., xanthan gum.

[0144] The foam phase, vesicle phase and hydrophilic phases are mixedtogether. Preferably, an equal amount of each phase is used in theformulation.

[0145] The foam phase, vesicle phase and hydrophilic phases can be mixedtogether in any order. For example, the foam phase and the vesicle phasecan be first mixed together, and then the resulting mixture can be mixedwith the hydrophilic phase. As another example, the foam phase can befirst mixed with the hydrophilic phase, and then the vesicle phase canbe added.

[0146] One or more active substances can be added to the foam phaseportion, the vesicle phase portion, the hydrophilic portion, or acombination of these portions.

[0147] The specific components of a formulation, and the formulationprocess, can be varied to obtain delivery systems which allow fordifferent rates of the release, and degrees of penetration, of activesubstance(s). For example, the phase of the system in which an activesubstance is placed affects release and penetration rates. For instance,to enhance penetration rates of either a hydrophilic or lipophilicactive substance, a major portion of the active substance is placedwithin the vesicle phase portion.

[0148] Another factor which affects release and penetration rates is thesize of the micro-compartments. The size of the vesicles can becontrolled via the formulation process. For example, during processing,as the homogenizing pressure and duration increases, the vesicle sizedecreases.

[0149] An additional factor which affects release and penetration ratesis the type of phospholipids used in the formulation. For example,penetration can be enhanced by including a greater portion ofunsaturated phospholipids within the formulation.

[0150] Also, phospholipids which include elevated levels of surfaceactive single chain agents enhance penetration. Surface active singlechain agents at about a level of 2% to 10% of the phospholipids areconsidered to be at an elevated level. Examples of surface active agentsare lysophospholipids.

[0151] An example of a phospholipid formulation comprises 95%phosphatidylcholine and 1.2% lysophosphatidylcholine. Such a formulationis sold as EPIKURON® 200 SH. A phospholipid formulation which providesenhanced penetration comprises 95% phosphatidylcholine and 3%lysophosphatidylcholine. Such a formulation is sold as EPIKURON® 200.

[0152] The concentration of free fatty acid is also an importantparameter affecting penetration rates. A relatively high level of freefatty acid enhances penetration of hydrophilic active substances.

[0153] Penetration rates can also be enhanced by the addition of certainadjuvants. For example, an anionic surfactant can be added to the foamphase portion. Also, incorporation of glyceryldilaurate into the vesiclebilayers creates more flexible vesicles which can enhance penetration.

[0154] Additional factors which affect release and penetration ratesinclude: the ratio between the different lipid components; the ratiobetween the foam phase, the vesicle phase and the hydrophilic phase; andthe ratio between the amounts of active substances within each phase.

[0155] In one embodiment of the present invention, the lipophiliccomponents of the delivery system form only two of the above-definedparticles. That is, the formulation comprises only the gas spheres andlipid particles; or the formulation comprises only the vesicles andlipid particles.

[0156] In this embodiment, the delivery system is produced from ahydrophilic portion and a lipophilic portion. The lipophilic portion ismade either into the foam phase or the vesicle phase, as describedabove. Preferably, the vesicle phase is produced under conditions whichdo not allow any gas to enter the formulation, such as in a vacuum. Thefoam phase or vesicle phase is mixed with the hydrophilic phase.Preferably, an equal amount of either the foam phase or vesicle phase,and the hydrophilic phase is used in the formulation.

[0157] Thus, while there have been described what are presently believedto be the preferred embodiments of the present invention, other andfurther embodiments, modifications, and improvements will be known tothose skilled in the art, and it is intended to include all such furtherembodiments, modifications, and improvements and come within the truescope of the claims as set forth below.

EXAMPLES Example 1

[0158] A General Method of Making:

[0159] The phospholipid, cholesterol, palmitic acid and ceramidecomponents are mixed together with water, and agitated at a temperatureof 70-80° C. The following additional components are added: mevalonicacid lactone, 25-hydroxycholecalciferol, propylene glycol, glycerine,PVP, TEA added along with water, and sodium hydroxide. Sodium hydroxideis added to adjust viscosity and stabilize the formulation. Water isthen added, and the formulation is agitated well. The formulation isthen cooled down.

[0160] An active substance can be dissolved in both the lipid phaseand/or the water phase, depending on the solubility and concentration ofthe active substance.

Example 2

[0161] Formulation of a Preferred Embodiment of the Topical DeliverySystem

[0162] (An active ingredient is excluded from this formulation.)Component Total amount Water 79.5% of formulation Epikuron 200SH 3.5% offormulation Palmitic acid 1.5% of formulation Cholesterol 1.5% offormulation Mevalonic acid 0.01% of formulation Triethanolamine 0.5% offormulation Phenonip 0.4% of formulation Xanthan gum 2.0% of formulationSkinflux 2.0% of formulation 25-hydroxycholecalciferol 0.0015% offormulation Propylene glycol 4.0% of formulation Glycerol 3.0% offormulation Polyvinylpyrrolidone 2.0% of formulation

[0163] Three fractions, a vesicle fraction, a foam fraction and ahydrophilic fraction, are first prepared separately, as described below.Each fraction weighs 3.3 kg. Then the three fractions are mixedtogether. The following tables show the percent amount of each componentcontributed by each fraction to the final formulation. Thus, for eachcomponent, the sum of the percent amounts of all the fractions is 100%.

[0164] 1: Vesicle Fraction Percent Amount in Final Component FormulationWater 33% of total water Hydrogenated lecithins 50% of total amountPalmitic acid 50% of total amount Cholesterol 50% of total amountMevalonic acid 50% of total amount Triethanol amine 50% of total amountPreservative (e.g., Paraben mixture) 50% of total amount Xanthan gum 15%of total amount Skinflux 33% of total amount 25-hydroxycholecalciferol50% of total amount 5M sodium hydroxide 1.3 ml per 1000 grams of water

[0165] In forming the vesicle fraction, the components are mixed andheated to the temperature range of 65 to 85° C. while gently stirring.The pH is set to the range of 5.5 to 8.2 by the use of sodium hydroxide.The resulting mixture is then homogenized. Homogenization can beaccomplished by, for example, a homogenizer set at a high pressure (e.g.10,000 to 40,000 psi); or by a sonicator. The size of the vesicles ispartially dependent upon how long the resulting mixture is agitated. Forexample, to obtain an average vesicle size of 0.140 μm, the resultingmixture is agitated for 60 minutes at about 70° C. The mixture is thenallowed to cool to below 40° C.

[0166] 2: Foam Fraction Percent Amount in Final Component FormulationWater 33% of total water Hydrogenated lecithins 50% of total amountPalmitic acid 50% of total amount Cholesterol 50% of total amountMevalonic acid 50% of total amount Triethanol amine 50% of total amountPreservative (e.g. a paraben mixture) 50% of total amount Xanthan gum7.5% of total amount Skinflux 33% of total amount25-hydroxycholecalciferol 50% of total amount 5M sodium hydroxide 1.3 mlper 1000 g of water

[0167] In forming the foam fraction, the components are mixed and heatedto the temperature range of 65 to 85° C. while stirring. The pH is setto the range of 5.5 to 8.2 by the use of sodium hydroxide. Thecomposition is mixed vigorously for 1 minute. Mixing can be done withULTRATURRAX® from IKA Werke, Janke & Kunkel GmbH & Co KG (Staufen,Germany). The composition is then allowed to cool to below 40° C.

[0168] 3: Hydrophilic Fraction Percent Amount in Final ComponentFormulation Water 34% of total water Propylene glycol 100% of totalamount Glycerol 100% of total amount Polyvinylpyrrolidone 100% of totalamount Xanthan gum 77.5% of total amount Skinflux 34% of total amount 5Msodium hydroxide 3.0 ml per 1000 g of water

[0169] In forming the hydrophilic fraction, the components are mixed andheated to the temperature range of 65 to 85° C. while stirring. The pHis set to the range of 5.5 to 8.2 by use of sodium hydroxide. Oncehomogeneous, the composition is then allowed to cool to below 40° C.

[0170] In forming the final formulation, after all the fractions arecooled down (below 40° C.), the three fractions are mixed together inany order. For example, the foam fraction is added to the vesiclefraction and gently mixed. Then the hydrophilic fraction is added. Theresulting mixture is gently blended for several minutes to obtain ahomogeneous solution.

[0171] The delivery system of this example is in the form of a cream. Inorder to produce a delivery system in an aerosol foam form, the totalamount of xanthan gum in the final formulation is reduced from 2% toabout 0.3%. Additionally, an emulsifier is added, such as laureth 4.Preferably, the emulsifier makes up about 0.7% of the final formulation.

Example 3

[0172] Formulation with Lidocaine as an Active Ingredient

[0173] An example of a 48 kg batch of a formulation of the deliverysystem follows. The three fractions used to prepare this formulationeach contain 16 kg. INCI Name Trade Name Supplier CAS AmountHydrogenated Epikuron Degussa  1.7 kg Lecithines 200 SH GoldschmidtCholesterol Vendico   57-88-5  0.8 kg Palmitic acid Karlshamn   57-10-3 0.8 kg Ceramide 1, 3, 6II, Skin Flux Degussa  1.0 kg Phytosphingosine,Goldschmidt Cholesterol, Sodium Lauroyl Lactylate, Carbomer, XanthanGum. Mevalonic acid Sigma  674-26-0  4.8 g lactone Aldrich 25-Hydroxy-Solvay 19356-17-3 0.72 kg cholecalciferol Propylene glycol MB-Sveda  57-55-6  2.0 kg Glycerin, 99.5% Vendico   56-81-5  1.5 kg Polyvinyl-Apoteket  9003-39-8  1.0 kg pyrrolidone Xanthan gum Sigma 11138-66-2 1.0 kg Aldrich Triethanolamine, MB-Sveda  102-71-6  0.3 kg 85% PhenonipVendico  0.2 kg Chemical Lidocain USP-grade Apoteket  2.4 kg Purified Upto Water   48 kg

Example 4

[0174] Measurement of Skin Barrier Restoration:

[0175] In the present context enhancing skin barrier restoration can bemeasured by tape and/or acetone striping of stratum corneum skin lipidcontent before, during and after a treatment period with the presentinvention and other systems. Then HPLC analysis of skin lipid content ofstratum corneum is conducted.

We claim:
 1. A water-based topical delivery system for an activesubstance, capable of enhancing skin barrier restoration in the stratumcorneum comprising water; fatty acids; cholesterol; and aceramide/phospholipid portion.
 2. A delivery system according to claim 1wherein the ratio of ceramide/phospholipid portion:cholesterol:fattyacid is approximately between 2:1:1 and 2.35:1:1.
 3. A delivery systemaccording to claim 1 further comprising at least one skin lipidprecursor.
 4. A delivery system according to claim 3 wherein the fattyacid is between 0.5-10%; the cholesterol is between 0.5-10%; the lipidprecursors are between 0.000001-10%; and the ceramide/phospholipidportion is between 0.005-20%.
 5. A delivery system according to claim Iwherein the fatty acid comprises ten to twenty-four carbon atoms.
 6. Adelivery system according to claim 5 wherein the fatty acid comprisessixteen to eighteen carbon atoms.
 7. A delivery system according toclaim I wherein the fatty acid is lauric acid, myristic acid, palmiticacid, stearic acid, arachidic acid, behenic acid, lignoceric acid, oleicacid, palmitoleic acid, linoleic acid, linolenic acid, arachidonic acid,precursors thereof, and/or unsaturated derivatives thereof, and/ormixtures thereof.
 8. A delivery system according to claim 1, whereinsaid fatty acid is selected from a group consisting of linoleic acid,γ-linolenic acid, homo-γ-linolenic acid, columbinic acid,eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, timnodonic acid,hexaenoic acid and mixtures thereof.
 9. A delivery system according toclaim 6 wherein the ceramide is ceramide 1, ceramide 3, ceramide 4,ceramide 5, ceramide 6A, a cerebroside, ceramide 6B, a pseudoceramide, aneoceramide, or mixtures thereof.
 10. A delivery system according toclaim 9 wherein the pseudoceramide isN-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl )hexadecanamide;N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)butanamide;N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)heptanamide;N-(2-hydroxyoctadecyl)-N-(2-bydroxyethyl)ethanamide;N-(2-hydroxyoctadecyl)-N-(2-O-glucopyranosyl)ethylpentanamide;N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)hexanamide;N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2butylhexanamide;N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)ethanamide;N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2-hydroxyhexanamide;N-(2-hydroxytetraadecyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxyhexadecyl)-N-(2-sulfoethyl)hexadecanamide;N-(2-hydroxyoctadecyl)-N-(2-phosphoethyl)butanamide;N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;N-(2-hydroxy-3-nonanyloxypropyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)butanamide;N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-sulfohydroxyethyl)decanamide;N-(2-hydroxy-3-decyloxypropyl)-N-(2-hydroxyethyl)hexanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)butanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)co-o-linoleoyldocosanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)-2-methylpropanamide;N-(2-hydroxy-3-tetraadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)heptanamide;N-(2-bydroxy-3-hexadecyloxypropyl)-N-(2-phosphoethyl)hexadecanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-)-glucopyranosyl)ethyl-2-hydroxypropanamide;or N-(2-hydroxy-3-octyloxypropyl)-N-(2-hydroxyethyl)pentanamide.
 11. Adelivery system according to claim 9 wherein the neoceramide is:N-(2,3-dihydroxypropyl)-N-(hexadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(tetradecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxypropanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(2-ethylhexadecyl)hexanamide;N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyoctanamide;N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(dodecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyhexanamide;N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)octanamide;N-(2-hydroxy-3-phosphopropyl)-N-(octadecyl)ethanamide;N-(2-hydroxy-3-sulfopropyl)-N-(hexadecyl)butanamide;N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)decanamide;N-(2,3-dihydroxypropyl)-N-(heptadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(heptadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(6-dodecenyl)hexadecan-amide;N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxy-ethanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)2-hydroxypropan-amide;N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(heptadecyl)-ethanamide;N-(2-hydroxy-3-sulfopropyl)-N-(dodecyl)heptanamide;N-(2,3-dihydroxypropyl)-N-(tetradecyl)-4-hydroxybutan-amide;N-(2,3-dihydroxypropyl)-N-(octadecyl)-(t)-O-linoleoyl-docosanamide;N-(2,3-dihydroxypropyl)-N-(linoleyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxy-heptan-amide;N-(2,3-dihydroxypropyl)-N-iyiodecyl)-(t)-O-linoleoyldocosanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)-3-hyrdoxybutanamide;N-(2-phospho-3hydroxypropyl)-N-(heptadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(2-methylheptadecyl)propanamide;N-(2,3-dihydroxypropyl)-N-(3-ethylheptadecyl)butanamide;N-(2-sulfo-3-hydroxypropyl)-N-(1-octadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)propanamide;N-(2,3-dihydroxypropyl)-N-(dodecyl)decanamide;N-(2,3-dihydroxypropyl)-N-(3-ethyldodecyl)butanamide;N-(2-O-glucopyranosyl-3-hydroxy propyl)-N-(heptadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxypropanamide;N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxyheptanamide;N-(2,3-dihydroxypropyl)-N-(dodecyl)-2-hydroxyoctanamide;N-(2,3-dihydroxypropyl)-N(hexadecyl)-2-methylheptanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)-2-hydroxypentanamide;N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxyheptanamide;N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxypropanamide; or N-(2;3-dihydroxypropyl)-N-(tetradecyl)ethanamide.
 12. A delivery systemaccording to claim 1, wherein said phospholipid is selected from a groupconsisting of phosphatidylcholine, DSPC 18, phosphatidic acid, inositolphosphate, phosphatidylglycerol, phosphatidylinositol,phosphatidylserine, phosphatidylethanolamine and mixtures thereof.
 13. Adelivery system according to claim 12, wherein said phospholipidcomprises at least one lysophospholipid.
 14. A delivery system accordingto claim 13 wherein the lysophospholipid is selected from the groupconsisting of monopalmitoylphosphatidylcholine (MPPC),lysophosphatidylcholines, lysophosphatidylglycerols,lysophosphatidylethanolamines, lysophosphatidylinositols,lysophosphatidylserines, lysophosphatidic acid, and mixtures thereof.15. A delivery system according to claim 3 wherein the lipid precursorcomprises mevalonic acid or 25-hydroxycholecalciferol.
 16. A deliverysystem according to claim 3 wherein the lipid precursor comprisesdeoxyacetein cimifugoside, adapalene, adenosine, aloe derived lectins,3-aminopropyl dihydrogen phosphate, anise extracts, ascorbic acid andderivatives thereof, ascorbyl palmitate, asiatic acid, benzoic acidderivatives, biotin, butanoyl betulinic acid, cathecholamines, coenzymeQ10, dehydrocholesterol, dehydroascorbic acid and derivatives thereof,estrogen and derivatives, eythrobic acid, genistein, lipoic acid,4-methoxy salicylic acid, N-acetyl cysteine, panthetine, pregnenoloneand derivatives, retinal, retinoates, retinal, retinyl acetate, retinylglucuronate, retinyl linoleate, retinyl palmitate, retinyl proprionate,phytosphingosine, or sphingosine.
 17. A delivery system according toclaim 1 further comprising triethanolamine.
 18. A delivery systemaccording to claim 1, wherein the water content exceeds 50%.
 19. Adelivery system according to claim 1, wherein the water content exceeds75%.
 20. A delivery system according to claim 1, wherein the watercontent exceeds 79%.
 21. A delivery system according to claim 1, whereinthe water content exceeds 90%.
 22. A delivery system according to claim3, wherein the combined content of a fatty acid, cholesterol, aceramide/phospholipid portion, and a skin lipid precursor in said systemis between about 2-20%.
 23. A delivery system according to claim 3,wherein the combined content of a fatty acid, cholesterol, aceramide/phospholipid portion, and a skin lipid precursor in said systemis between about 5-20%.
 24. A delivery system according to claim 3,wherein the combined content of a fatty acid, cholesterol, aceramide/phospholipid portion, and a skin lipid precursor in said systemis between about 5-15%.
 25. A delivery system according to claim 3,wherein the combined content of a fatty acid, cholesterol, aceramide/phospholipid portion, and a skin lipid precursor in said systemis between about 6-13%.
 26. A delivery system according to claim 3,comprising a combination of: Fatty Acid 0.5-10% Phospholipid 0.5-10%Cholesterol 0.5-7% Lipid precursor 0.000001-10% Ceramide 0.005%-7%.


27. A delivery system according to claim 26 wherein the lipid precursoris mevalonic acid.
 28. A delivery system according to claim 26, furthercomprising Glycerine 0-5% Propylene glycol 0-48% PVP (M weight 40.000)0-5% TEA 0-3%.


29. A delivery system according to claim 26, further comprising25-Hydroxycholecalciferol 0.015% Acylceramides 0.025%.


30. A delivery system according to claim 26, wherein the lipid precursorcomprises 0.01% of Mevalonic acid, 0.0015% 25-Hydroxycholecalciferol, ora combination of Mevalonic acid, and 25-Hydroxycholecalciferol.
 31. Adelivery system according to claim 3, wherein said skin barrierrestoration is enhanced by in situ promotion of cholesterol synthesis inthe stratum corneum.
 32. A delivery system according to claim 3, whereinsaid skin barrier restoration is enhanced by in situ promotion ofceramide synthesis in the stratum corneum.
 33. A delivery systemaccording to claim 3, wherein said skin barrier restoration is enhancedby in situ promotion of sphingolipid synthesis in the stratum corneum.34. A delivery system according to claim 1, wherein said system furthercomprises one or more therapeutically active substances selected fromthe group consisting of peptides, proteins, sunscreens, tanning agents,skin anti-wrinkling agents, anti-dandruff agents, anti-acne agents, hairgrowth stimulants, hormones, vaccines, nicotine, interferon, painkillers, vitamins; and substances which treat eczema, dry skin, itchyskin, fungal infections, acne, skin cancer, hair loss, louse infections,psoriasis, and skin lesions.
 35. A delivery system according to claim 3,wherein the lipids of said system blend with the lipids present in thecornea stratum, resulting in a temporary and reversible atrophy in thelipid bilayer, thereby enhancing possibility for penetration oftherapeutic substances delivered by the system.
 36. A delivery systemaccording to claim 3, wherein the system does not comprise alcohol. 37.A delivery system according to claim 36, wherein the alcohol is ethanol.38. A delivery system according to claim 3, wherein the system comprisesless than 10% alcohol.
 39. A delivery system according to claim 38wherein the alcohol is ethanol.
 40. A topical delivery system for anactive substance comprising water and lipophilic components, wherein thelipophilic components comprise fatty acids, cholesterol, and aceramide/phospholipid portion, and wherein the lipophilic components arein the form of lipid particles, and gas spheres or vesicles.
 41. Atopical delivery system according to claim 40 further comprising atleast one skin lipid precursor.
 42. A topical delivery system for anactive substance comprising water and lipophilic components, wherein thelipophilic components comprise fatty acids, cholesterol, and aceramide/phospholipid portion, and wherein the lipophilic components arein the form of lipid particles, gas spheres and vesicles.
 43. A topicaldelivery system according to claim 42 further comprising at least oneskin lipid precursor.
 44. A topical delivery system according to claim40 wherein the diameter of the gas spheres is approximately 1 μm to 500μm.
 45. A topical delivery system according to claim 40 wherein thediameter of the vesicles is approximately 0.02 μm to 0.5 μm.
 46. Atopical delivery system according to claim 40 wherein the diameter ofthe lipid particles is approximately less than 1 μm to 150 μm.
 47. Adelivery system according to claim 41 wherein the fatty acid is between0.5-10%; the cholesterol is between 0.5-10%; the lipid precursors arebetween 0.000001-10%; and the ceramide/phospholipid portion is between0.005-20%.
 48. A delivery system according to claim 40 wherein the fattyacid comprises ten to twenty-four carbon atoms.
 49. A delivery systemaccording to claim 48 wherein the fatty acid comprises sixteen toeighteen carbon atoms.
 50. A delivery system according to claim 40wherein the fatty acid is lauric acid, myristic acid, palmitic acid,stearic acid, arachidic acid, behenic acid, lignoceric acid, oleic acid,palmitoleic acid, linoleic acid, linolenic acid, arachidonic acid,precursors thereof, and/or unsaturated derivatives thereof, and/ormixtures thereof.
 51. A delivery system according to claim 40, whereinsaid fatty acid is selected from a group consisting of linoleic acid,γ-linolenic acid, homo-γ-linolenic acid, columbinic acid,eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, timnodonic acid,hexaenoic acid and mixtures thereof.
 52. A delivery system according toclaim 43 wherein the ceramide is ceramide 1, ceramide 3, ceramide 4,ceramide 5, ceramide 6A, a cerebroside, ceramide 6B, a pseudoceramide, aneoceramide, or mixtures thereof.
 53. A delivery system according toclaim 52 wherein the pseudoceramide isN-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl )hexadecanamide;N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)butanamide;N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)heptanamide;N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)ethanamide;N-(2-hydroxyoctadecyl)-N-(2-O-glucopyranosyl)ethylpentanamide;N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)hexanamide;N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2butylhexanamide;N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)ethanamide;N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2-hydroxyhexanamide;N-(2-hydroxytetraadecyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxyhexadecyl)-N-(2-sulfoethyl)hexadecanamide;N-(2-hydroxyoctadecyl)-N-(2-phosphoethyl)butanamide;N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;N-(2-hydroxy-3-nonanyloxypropyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)butanamide;N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-sulfohydroxyethyl)decanamide;N-(2-hydroxy-3-decyloxypropyl)-N-(2-hydroxyethyl)hexanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-bydroxyethyl)hexadecanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)butanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)co-o-linoleoyldocosanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)-2-methylpropanamide;N-(2-hydroxy-3-tetraadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)heptanamide;N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-phosphoethyl)hexadecanamide;N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-)-glucopyranosyl)ethyl-2-hydroxypropanamide;or N-(2-hydroxy-3-octyloxypropyl)-N-(2-hydroxyethyl)pentanamide.
 54. Adelivery system according to claim 52 wherein the neoceramide is:N-(2,3-dihydroxypropyl)-N-(hexadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(tetradecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxypropanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(2-ethylhexadecyl)hexanamide;N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyoctanamide;N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(dodecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyhexanamide;N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)octanamide;N-(2-hydroxy-3-phosphopropyl)-N-(octadecyl)ethanamide;N-(2-hydroxy-3-sulfopropyl)-N-(hexadecyl)butanamide;N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)decanamide;N-(2,3-dihydroxypropyl)-N-(heptadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(heptadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(6-dodecenyl)hexadecan-amide;N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxy-ethanamide;N-(2,3-dihydroxypropyl)-N-(cctadecyl)2-hydroxypropan-amide;N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(heptadecyl)-ethanamide;N-(2-hydroxy-3-sulfopropyl)-N-(dodecyl)heptanamide;N-(2,3-dihydroxypropyl)-N-(tetradecyl)-4-hydroxybutan-amide;N-(2,3-dihydroxypropyl)-N-(octadecyl)-(t)-O-linoleoyl-docosanamide;N-(2,3-dihydroxypropyl)-N-(linoleyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxy-heptan-amide;N-(2,3-dihydroxypropyl)-N-iyiodecyl)-(t)-O-linoleoyldocosanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)-3-hyrdoxybutanamide;N-(2-phospho-3hydroxypropyl)-N-(heptadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(2-methylheptadecyl)propanamide;N-(2,3-dihydroxypropyl)-N-(3-ethylheptadecyl)butanamide;N-(2-sulfo-3-hydroxypropyl)-N-(1-octadecyl)ethanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)propanamide;N-(2,3-dihydroxypropyl)-N-(dodecyl)decanamide;N-(2,3-dihydroxypropyl)-N-(3-ethyldodecyl)butanamide;N-(2-O-glucopyranosyl-3-hydroxy propyl)-N-(heptadecyl)butanamide;N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxypropanamide;N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxyheptanamide;N-(2,3-dihydroxypropyl)-N-(dodecyl)-2-hydroxyoctanamide;N-(2,3-dihydroxypropyl)-N(hexadecyl)-2-methylheptanamide;N-(2,3-dihydroxypropyl)-N-(octadecyl)-2-hydroxypentanamide;N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxyheptanamide;N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxypropanamide; orN-(2;3-dihydroxypropyl)-N-(tetradecyl)ethanamide.
 55. A delivery systemaccording to claim 40, wherein said phospholipid is selected from agroup consisting of phosphatidylcholine, DSPC 18, phosphatidic acid,inositol phosphate, phosphatidylglycerol, phosphatidylinositol,phosphatidylserine, phosphatidylethanolamine and mixtures thereof.
 56. Adelivery system according to claim 55, wherein the phospholipidscomprises at least one lysophospholipid.
 57. A delivery system accordingto claim 56 wherein the lysophospholipid is selected from the groupconsisting of monopalmitoylphosphatidylcholine (MPPC),lysophosphatidylcholines, lysophosphatidylglycerols,lysophosphatidylethanolamines, lysophosphatidylinositols,lysophosphatidylserines, lysophosphatidic acid, and mixtures thereof.58. A delivery system according to claim 41 wherein the lipid precursorcomprises mevalonic acid or 25-hydroxycholecalciferol.
 59. A deliverysystem according to claim 41 wherein the lipid precursor comprisesdeoxyacetein cimifugoside, adapalene, adenosine, aloe derived lectins,3-aminopropyl dihydrogen phosphate, anise extracts, ascorbic acid andderivatives thereof, ascorbyl palmitate, asiatic acid, benzoic acidderivatives, biotin, butanoyl betulinic acid, cathecholamines, coenzymeQ10, dehydrocholesterol, dehydroascorbic acid and derivatives thereof,estrogen and derivatives, eythrobic acid, genistein, lipoic acid,4-methoxy salicylic acid, N-acetyl cysteine, panthetine, pregnenoloneand derivatives, retinal, retinoates, retinal, retinyl acetate, retinylglucuronate, retinyl linoleate, retinyl palmitate, retinyl proprionate,phytosphingosine, or sphingosine.
 60. A delivery system according toclaim 40 further comprising triethanolamine.
 61. A delivery systemaccording to claim 40, wherein the water content exceeds 50%.
 62. Adelivery system according to claim 40, wherein the water content exceeds75%.
 63. A delivery system according to claim 40, wherein the watercontent exceeds 79%.
 64. A delivery system according to claim 40,wherein the water content exceeds 90%.
 65. A delivery system accordingto claim 40, wherein the combined content of a fatty acid, cholesterol,a ceramide/phospholipid portion, and a skin lipid precursor in saidsystem is between about 2-20%.
 66. A delivery system according to claim41, wherein the combined content of a fatty acid, cholesterol, aceramide/phospholipid portion, and a skin lipid precursor in said systemis between about 5-20%.
 67. A delivery system according to claim 41,wherein the combined content of a fatty acid, cholesterol, aceramide/phospholipid portion, and a skin lipid precursor in said systemis between about 5-15%.
 68. A delivery system according to claim 41,wherein the combined content of a fatty acid, cholesterol, aceramide/phospholipid portion, and a skin lipid precursor in said systemis between about 6-13%.
 69. A delivery system according to claim 41,comprising a combination of: Fatty Acid 0.5-10% Phospholipid 0.5-10%Cholesterol 0.5-7% Lipid precursor 0.000001-10% Ceramide 0.005% -7%.


70. A delivery system according to claim 69 wherein the lipid precursoris mevalonic acid.
 71. A delivery system according to claim 69, furthercomprising Glycerine 0-5% Propylene glycol 0-48% PVP (M weight 40.000)0-5% TEA 0-3%.


72. A delivery system according to claim 69, wherein the lipid precursorcomprises 0.01% of Mevalonic acid; 0.0015% of 25-Hydroxycholecalciferolor a mixture of both.
 73. A delivery system according to claim 41,wherein said skin barrier restoration is enhanced by in situ promotionof cholesterol synthesis in the stratum corneum.
 74. A delivery systemaccording to claim 41, wherein said skin barrier restoration is enhancedby in situ promotion of ceramide synthesis in the stratum corneum.
 75. Adelivery system according to claim 41, wherein said skin barrierrestoration is enhanced by in situ promotion of sphingolipid synthesisin the stratum corneum.
 76. A delivery system according to claim 40,wherein said system further comprises one or more therapeutically activesubstances selected from the group consisting of: peptides, proteins,sunscreens, tanning agents, skin anti-wrinkling agents, anti-dandruffagents, anti-acne agents, hair growth stimulants, hormones, vaccines,nicotine, interferon, pain killers, vitamins; and substances which treateczema, dry skin, itchy skin, fungal infections, acne, skin cancer, hairloss, louse infections, psoriasis, and skin lesions.
 77. A deliverysystem according to claim 40, wherein the system does not comprisealcohol.
 78. A delivery system according to claim 77, wherein thealcohol is ethanol.
 79. A delivery system according to claim 40, whereinthe system comprises less than 10% alcohol.
 80. A delivery systemaccording to claim 79 wherein the alcohol is ethanol.